Phenylalanyl-tRNA synthetase deficiency caused by biallelic variants in FARSA gene and literature review.

Background: Aminoacyl-tRNA synthetases (ARSs) are indispensable enzymes for protein biosynthesis in cells. The phenylalanyl-tRNA synthetase (FARS1) located in cytoplasm which consists of two FARS alpha subunits (FARSA) and two FARS beta subunits (FARSB). Autosomal recessive inheritance of pathogenic variants of FARSA or FARSB can result in defective FARS1 which are characterized by interstitial lung disease, liver disease, brain abnormalities, facial dysmorphism and growth restriction.

A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P and causes lysosome acidification and hypopigmentation.

Albinism is a group of inherited disorders mainly affecting skin, hair and eyes. Here we identify a de novo point mutation, p.R210C, in the TPCN2 gene which encodes Two Pore Channel 2 (TPC2) from a patient with albinism.

Identification of a novel variant in N-cadherin associated with dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM), which is a major cause of heart failure, is a primary cardiac muscle disease with high morbidity and mortality rates. DCM is a genetically heritable disease and more than 10 gene ontologies have been implicated in DCM. encodes N-cadherin and belongs to a superfamily of transmembrane proteins that mediate cell-cell adhesion in a calcium-dependent manner.

New insights into the pathogenesis of Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is characterized by defects of multiple tissue-specific lysosome-related organelles (LROs), typically manifesting with oculocutaneous albinism or ocular albinism, bleeding tendency, and in some cases with pulmonary fibrosis, inflammatory bowel disease or immunodeficiency, neuropsychological disorders. Eleven HPS subtypes in humans and at least 15 subtypes in mice have been molecularly identified. Current understanding of the underlying mechanisms of HPS is focusing on the defective biogenesis of LROs.

Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4.

Background: Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis.

[Identification of variants in TNNI3 gene in two children with restrictive cardiomyopathy].

Objective: To identify the pathogenesis in two patients of restrictive cardiomyopathy (RCM) using high-throughput sequencing.

Methods: Peripheral blood samples from the two patients and their parents were collected and genomic DNAs were extracted to conduct targeted next generation sequencing or whole exome sequencing. Bioinformation analysis was performed to identify the pathogenic variants in genes associated with cardiomyopathy, which were further validated by Sanger sequencing.

A zinc transporter, transmembrane protein 163, is critical for the biogenesis of platelet dense granules.

Lysosome-related organelles (LROs) are a category of secretory organelles enriched with ions such as calcium, which are maintained by ion transporters or channels. Homeostasis of these ions is important for LRO biogenesis and secretion. Hermansky-Pudlak syndrome (HPS) is a recessive disorder with defects in multiple LROs, typically platelet dense granules (DGs) and melanosomes.

Mycobacterium tuberculosis infection up-regulates MFN2 expression to promote NLRP3 inflammasome formation.

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation.

Whole exome sequencing for non-selective pediatric patients with hyperlipidemia.

Background: Hyperlipidemia is a group of conditions with abnormally elevated levels of any or all lipids or lipoproteins in the blood. It is highly heterogeneous both genetically and clinically, which contributes to diagnostic challenges and results in many patients to be underdiagnosed and undertreated in China. Precise diagnosis and early management are critical to reduce the incidence of potential coronary artery disease and cardiovascular disease.

Whole-exome sequencing reveals two variants in the gene in two Chinese patients with left ventricular non-compaction cardiomyopathy.

Importance: Pathogenic variants in the gene are associated with aggressive dilated cardiomyopathy (DCM). Recently, was found to be associated with left ventricular non-compaction cardiomyopathy (LVNC). Thus far, only five families with LVNC have been reported to carry variants in .

Targeting Histone Deacetylase 6 Reprograms Interleukin-17-Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma.

Background And Aims: Hepatocellular carcinoma (HCC) is often accompanied by resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. We report that histone deacetylase 6 (HDAC6) represses interleukin-17 (IL-17)-producing helper T (T 17) cell pathogenicity and the antitumor immune response, dependent on its deacetylase activity.

Approach And Results: Adoptive transfer of HDAC6-deficient T 17 cells impedes HCC growth, dependent on elevated IL-17A, by enhancing the production of antitumor cytokine and cluster of differentiation 8-positive (CD8+) T cell-mediated antitumor responses.

Sorting machineries: how platelet-dense granules differ from α-granules.

Platelets respond to vascular injury via surface receptor stimulation and signaling events to trigger aggregation, procoagulant activation, and granule secretion during hemostasis, thrombosis, and vascular remodeling. Platelets contain three major types of secretory granules including dense granules (or δ-granules, DGs), α-granules (AGs), and lysosomes. The contents of platelet granules are specific.

HDAC6-mediated acetylation of lipid droplet-binding protein CIDEC regulates fat-induced lipid storage.

Obesity is characterized by aberrant fat accumulation. However, the intracellular signaling pathway that senses dietary fat and leads to fat storage remains elusive. Here, we have observed that the levels of histone deacetylase 6 (HDAC6) and the related family member HDAC10 are markedly reduced in adipose tissues of obese animals and humans.

Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids.

Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids.

P-glycoprotein substrate models using support vector machines based on a comprehensive data set.

P-glycoprotein (P-gp) is one of the major ABC transporters and involved in many essential processes such as lipid and steroid transport across cell membranes but also in the uptake of drugs such as HIV protease and reverse transcriptase inhibitors. Despite its importance, reliable models predicting substrates of P-gp are scarce. In this study, we have built several computational models to predict whether or not a compound is a P-gp substrate, based on the largest data set yet published, employing 332 distinct structures.

Emodin-induced apoptosis through p53-dependent pathway in human hepatoma cells.

Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible cells. However, the signaling pathway of their apoptotic effects remains undefined. In this study, the cytotoxic effect of emodin on various human hepatoma cell lines was investigated.